ArticleAlcoholism, clinical and experimental research2016
Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus-Infected Liver Cells by Up-Regulating USP18.
Article in Alcoholism, clinical and experimental research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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36 citing papers in PubMed, 51 citations in OpenAlex.
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- Deubiquitinases in liver diseases: from mechanisms to targeted therapy.Science China. Life sciences · 2026Review
- Porcine reproductive and respiratory syndrome virus NSP5 exploited UBE2L6 to promote viral replication via antagonising host RLRs and ISGylation.Veterinary research · 2025Article
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- Roles of ubiquitin-specific proteases in inflammatory diseases.Frontiers in immunology · 2024Review
- ISG15: its roles in SARS-CoV-2 and other viral infections.Trends in microbiology · 2023Review
- Protein ISGylation: a posttranslational modification with implications for malignant neoplasms.Exploration of targeted anti-tumor therapy · 2023Review
- Interferon-stimulated gene 15 facilitates BTV replication through interacting with the NS1 protein.Frontiers in microbiology · 2023Article
- The diverse repertoire of ISG15: more intricate than initially thought.Experimental & molecular medicine · 2022Review
- Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells.Biomolecules · 2021Article
- Beneficial Effects of Betaine: A Comprehensive Review.Biology · 2021Review
- Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway.Cellular and molecular life sciences : CMLS · 2021Review
- Alcohol-and-HIV-Induced Lysosomal Dysfunction Regulates Extracellular Vesicles SecretionBiology · 2021Article
- Second hits exacerbate alcohol-related organ damage: an update.Alcohol and alcoholism (Oxford, Oxfordshire) · 2021Review
- Crosstalk Between SUMO and Ubiquitin-Like Proteins: Implication for Antiviral Defense.Frontiers in cell and developmental biology · 2021Review
- Proteomics Mapping of the ISGylation Landscape in Innate Immunity.Frontiers in immunology · 2021Review
- ISGylation in Innate Antiviral Immunity and Pathogen Defense Responses: A Review.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundAlcohol consumption exacerbates the pathogenesis of hepatitis C virus (HCV) infection and worsens disease outcomes. The exact reasons are not clear yet, but they might be partially attributed to the ability of alcohol to further suppress the innate immunity. Innate immunity is known to be already decreased by HCV in liver cells.
methodsIn this study, we aimed to explore the mechanisms of how alcohol metabolism dysregulates IFNα signaling (STAT1 phosphorylation) in HCV
resultsContinuously produced Ach suppressed IFNα-induced STAT1 phosphorylation, but increased the level of a protease, USP18 (both measured by Western blot), which interferes with IFNα signaling. Induction of USP18 by Ach was confirmed in primary human hepatocyte cultures and in livers of ethanol-fed HCV transgenic mice. Silencing of USP18 by specific siRNA attenuated the pSTAT1 suppression by Ach. The mechanism by which Ach down-regulates pSTAT1 is related to an enhanced interaction between IFNαR2 and USP18 that finally dysregulates the cross talk between the IFN receptor on the cell surface and STAT1. Furthermore, Ach decreases ISGylation of STAT1 (protein conjugation of a small ubiquitin-like modifier, ISG15, Western blot), which preserves STAT1 activation. Suppressed ISGylation leads to an increase in STAT1 K48 polyubiquitination which allows pSTAT1 degrading by proteasome.
conclusionsWe conclude that Ach disrupts IFNα-induced STAT1 phosphorylation by the up-regulation of USP18 to block the innate immunity protection in HCV-infected liver cells, thereby contributing to HCV-alcohol pathogenesis. This, in part, may explain the mechanism of HCV-infection exacerbation/progression in alcohol-abusing patients.
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